Robert T. Abraham, Ph.D. (Program Leader) The Signal Transduction Program focuses on the biochemical pathways that regulate cellular responses to mitogenic and stress-inducing stimuli. Abnormalities in signal transduetion are universal features of human cancer cells, and underlie virtually all aspects of the transformed phenotype, including uncontrolled growth, immortality, genetic instability, and tissue invasiveness. Moreover, components of the abnormal signaling machinery are considered primary targets for drug discovery; hence, signal transduction research notably provides eritical insights into cancer biology, but also uncovers novel strategies for cancer prevention and therapy. Members of the Signal Transduction Research Program currently pursue three major investigative areas: (1) T lymphocyte biology, with a particular emphasis on the signaling proliferation, differentiation, and apoptosis; (2) mitogenic and stress-induced signaling pathways in normal and transformed cells, with established interests in growthregulatory kinases and phosphatases, including the PI 3-kinase - AKT - roTOR signaline cascade; (3) "internal" signaling events related to the control of DNA replication and mitosis, and to the detection and repair of DNA damage. Because cell signaling research permeates all aspects of cancer biology, an important goal for the next funding period is to build on our existing network of interactions with other scientific programs in the Cancer Center. From the scientific perspective, we intend to integrate chemical biology into our existing expertise in cell and structural biology. Our objective is to add pharmacologically active compounds to the existing battery of genetic and biochemical tools currently used by our members to probe intracellular signaling mechanisms. A related objective is that the Signal Transduction Program will be a major contributor to the Cancer Center's Drug Discovery Initiative. In addition, we view this program as one that will add critical strengths to the Cancer Center in the areas of cell cycle regulation, genome surveillance, and cellular responses to hypoxia and other forms of stress.